EP1370266A1 - Methode de traitement - Google Patents

Methode de traitement

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Publication number
EP1370266A1
EP1370266A1 EP02704036A EP02704036A EP1370266A1 EP 1370266 A1 EP1370266 A1 EP 1370266A1 EP 02704036 A EP02704036 A EP 02704036A EP 02704036 A EP02704036 A EP 02704036A EP 1370266 A1 EP1370266 A1 EP 1370266A1
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EP
European Patent Office
Prior art keywords
alkyl
formula
ring
hydrogen
membered
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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EP02704036A
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German (de)
English (en)
Inventor
Andrew AstraZeneca R & D Alderley HUGHES
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AstraZeneca AB
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AstraZeneca AB
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Publication of EP1370266A1 publication Critical patent/EP1370266A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Definitions

  • This invention relates to therapeutic agents, and in particular to a method of using compounds such as EPl antagonists, for reducing uric acid levels in a warm-blooded animal, such as a human.
  • Uric acid is a naturally occurring organic compound in a warm-blooded animal, occurring as a product of the metabolism of naturally occurring purines. Hyperuricemia, or raised uric acid concentrations in serum or plasma, may result from diminished renal excretion of uric acid, from elevated biosynthesis of uric acid or from abnormal metabolic (either anabolic or catabolic) processes.
  • the disorder can be congenital, occurring secondary to inborn errors of metabolism, or may be acquired, as in elevated uric acid levels due to dietary composition, diminished excretion due to renal insufficiency, in neoplastic diseases such as leukemia, Burkitt's lymphoma and other cancers, or due to the cytotoxic effects of cancer chemotherapy or radiation therapy which result in an elevated level of products of cell lysis including purines which are metabolically converted to uric acid.
  • Inborn errors of metabolism include the Lesch-Nyhan syndrome, phosphoribosyl pyrophosphate synthetase overactivity and glucose-6-phosphatase deficiency.
  • a diminished renal excretion of uric acid can occur as a result of renal disease, certain drug therapies including administration of diuretics, and may accompany diseases such as hyperparathyroidism.
  • Increased production of uric acid is a known accompanying feature of administration of cytotoxic agents or of therapeutic radiation treatment as in the treatment of cancers, including lymphomas, leukemia, and solid tumors.
  • This manifestation of hyperuricemia is a subset of a group of metabolic disorders collectively termed acute tumor lysis syndrome.
  • acute tumor lysis syndrome As this relates to elevated uric acid levels, rapid lysis of cells results in an acute release into the circulation, of intracellular contents, including endogenous purines which are metabolic precursers to uric acid. These purines are converted by enzymes such as xanthine oxidase into uric acid.
  • hyperuricemia includes crystal arthropathy, gout and accompanying depositions of crystal deposits in other organs including tophi in the skin and tendons; and may occur as an associative factor in obesity, diabetes mellitus, hypertension, ischemic heart disease and hyperlipoproteinemia.
  • Precipitation of uric acid generally as crystals of monosodium urate in soft tissues is strongly associated with elevated levels of uric acid.
  • the saturation level of uric acid in extracellular fluid at 37°C has been measured at 0.4mmol/L and thus is a target urate level for treatment of diseases associated with hyperuricemia such as gout wherein symptoms of the disease are mediated via crystalline deposits of uric acid or monosodium urate. Below this target level, preferably at levels from 0.25-0.35 mmol/L, crystalline deposits can effectively be redissolved and further crystallization can be prevented.
  • Diseases associated with elevated uric acid levels include, but are not limited to, gout, gouty arthritis, trophi, hyperuricemia associated with a congenital abnormality in the metabolism of xanthine oxidase, urate nephropathy incident to hyperuricemia, or hyperuricemia incident to therapeutic use of cytotoxic chemotherapy or radiation therapy.
  • Allopurinol is commonly used to block the production of uric acid, although its use is limited by side effects, the most prominent being skin rashes and hypersensitivity which can be both disabling and at times life-threatening. As such, prescribers are warned to discontinue medication if a skin rash occurs. Hepatotoxicity can also accompany allopurinol use. Drugs which are used to increase the elimination of uric acid such as probenecid and sulfinopyrazone also suffer from similar side effects.
  • EPl antagonists are compounds which are antagonists of E-type prostaglandins, in particular PGE 2 .
  • the EPl receptor has been found to be involved in pain generation, and thus antagonists of the EPl receptor have been sought as potential therapies for pain management.
  • the present invention provides a method of reducing uric acid levels in a warm-blooded animal comprising administering to said animal an effective amount of an EPl antagonist.
  • the present invention also provides a method of treating hyperuricemia in a warmblooded animal, comprising administering to said animal a therapeutically effective amount of an EPl antagonist.
  • a method of treating or preventing a disease caused by hyperuricemia in a warm-blooded animal comprising administering to the animal suffering from said disease a therapeutically effective amount of an EPl antagonist.
  • Typical EPl antagonists useful in the practice of the current invention include the compounds described in WO 97/00863; WO 97/00864; WO 00/69465; EP 0480641; EP 0534667; WO 96/03380; WO 96/06822; EPA 0733033; EPA 0847391; EPA 0835246 and EPA 0752421.
  • the contents of the aforesaid European and International Patent Applications are hereby incorporated by reference.
  • EPl antagonists that can be used to practice the methods of the current invention are those described in US 5,504,077; EP 694546; US 5,441,950; US 5,420,270; US 5,354,747; US 5,354,746; US 5,324,722; US 5,304,644; US 5,281,590; WO 9313082; EP 539977; WO 9307132; EP 512400; EP 512399; EP 218077; EP 193822; US 4,132,847; EP 0878465; EP 0300676; US 4,775,680; EP 0845451; EP 0160408; US 4,820,689 and WO 9827053.
  • the contents of the aforesaid US, European and International Patents and Applications are hereby incorporated by reference.
  • Particular compounds that may be used in this invention include compounds of formula I and formula II:
  • A is an optionally substituted: phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl or thiadiazolyl having at least two adjacent ring carbon atoms;
  • the -CH(R 3 )N(R )B-R 1 and -OR 4 groups of formula I are positioned in a 1 ,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the OR 4 linking group of formula I or the OD linking group of formula II (and therefore in the 3-position relative to the -CHR ⁇ NR ⁇ - linking group) is not substituted;
  • R! is positioned on ring B in a 1,3 or 1,4 relationship with the -CH(R3)N(R2)- linking group and is carboxy, carboxyC 1.3 alkyl, tetrazolyl, tetrazolylC ⁇ alkyl, tetronic acid, hydroxamic acid, sulfonic acid, or R! is of the formula -CONR a R a ⁇ wherein R a is hydrogen or Cj.galkyl and R a ⁇ is hydrogen, Cj.galkyl (optionally substituted by halo, amino, Cj.
  • R D is Cj.galkyl (optionally substituted by halo, hydroxy, nitro, cyano, trifiuoromethyl, C ⁇ _4alkoxy, amino, Ci ⁇ alkylamino, di-Ci ⁇ alkylamino or C ⁇ alkoxycarbonyl), C2-6 a lkenyl (provided the double bond is not in the 1 -position), C2_6alkynyl (provided the triple bond is not in the 1 -position), 5- or 6-membered heterocyclylC ⁇ _3alkyl, 5- or 6-membered heteroarylC ⁇ _3alkyl, phenylC 1 _3alkyl, 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl or phenyl; wherein any heterocyclyl or heteroaryl group in R & 1 is optionally substituted by halo, hydroxy, nitro, cyano
  • R 1 is of the formula -SO2N(R c )R cl , wherein R c is hydrogen or
  • R cl is hydrogen or or R 1 is of the formula (IA), (IB) or (IC):
  • X is CH or nitrogen
  • Y is oxygen or sulfur
  • Y' is oxygen or NR d
  • Z is CH 2 , NR d or oxygen provided that there is no more than one ring oxygen and there are at least two ring heteroatoms and wherein R d is hydrogen or
  • R2 is hydrogen, C ⁇ .galkyl, optionally substituted by hydroxy, cyano or trifiuoromethyl, C2-6&lkenyl (provided the double bond is not in the 1 -position), C2-6 a lkynyl (provided the triple bond is not in the 1 -position), phenylC 1.3 alkyl or pyridylC 1.3 alkyl.
  • R3 is hydrogen, methyl or ethyl.
  • R 4 of formula I is optionally substituted: Ci .galkyl, C 3 . 7 cycloalkylC]. alkyl or C . cycloalkyl;
  • D of formula II is hydrogen, an optionally substituted 5-7 membered carbocyclic ring containing one double bond, C].
  • R5 is independently selected from hydrogen, methyl or ethyl
  • R6 is hydrogen, methyl, bromo, chloro, fluoro or trifiuoromethyl
  • R is hydrogen, bromo, chloro, fluoro or trifiuoromethyl
  • R8 is hydrogen, C ⁇ a-kyl, bromo, chloro, fluoro or trifiuoromethyl
  • n 0 or 1 ;
  • a 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1 , 2 or 3 ring atoms are selected from nitrogen, oxygen and sulfur.
  • a 5- or 6-membered heterocyclic ring is a ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulfur.
  • Particular 5- or 6-membered monocyclic heteroaryl rings include py ⁇ olyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.
  • Particular 5- or 6-membered heterocyclic ring systems include pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and morpholinyl.
  • a ring nitrogen atom in A can be substituted without becoming quaternized, it is unsubstituted or substituted by C1.4a.kyl.
  • Particular substituents for ring carbon atoms in B include halo, trifiuoromethyl, nitro, hydroxy, Cj.galkoxy, C ⁇ .galkyl, amino, C ⁇ _4alkylamino, di(C ⁇ _4alkyl)amino, cyano,
  • a ring nitrogen atom in B can be substituted without becoming quaternized, it is unsubstituted or substituted by C ⁇ _4alkyl.
  • alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl and functional groups on alkyl chains may be anywhere on the chain, for example hydroxyiminoC 1.galkyl includes 1 -(hydroxyimino)propyl and 2-(hydroxyimino)propyl.
  • C ⁇ - 6 alkyl substituted by halo includes trifiuoromethyl.
  • substituents for the 5-7 membered carbocyclic ring containing one double bond include Ci ⁇ alkyl, C - 4 alkenyl, C . 4 alkynyl, halo, hydroxy, amino, C ⁇ -- ⁇ alkylamino, di-(C ⁇ - 4 alkyl)amino, cyano, trifiuoromethyl, oxo, carboxy and carbamoyl.
  • Amino acid residues formed from R a and R al together with the nitrogen to which they are attached include residues (-NHCH(R)COOH) derived from naturally-occurring and non- naturally-occurring amino acids.
  • suitable amino acids include glycine, alanine, serine, threonine, phenylalanine, glutamic acid, tyrosine, lysine and dimethylglycine.
  • Suitable ring systems of the formula (IA), (IB), or (IC) include 5-oxo-4,5-dihydro-
  • Ci .galkoxycarbonyl are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxyC ⁇ alkyl are carboxymethyl, 2-carboxyethyl,
  • examples of Ci.galkoxycarbonylC ⁇ alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolylC 1.3 alkyl are tetrazolylmethyl and 2-tetrazolyl ethyl; examples of Cj ⁇ alkoxy are methoxy, ethoxy, propoxy and isopropoxy; examples of C2_6alkenyl are vinyl and allyl; examples of C2-6 a lkynyl are ethynyl and propynyl; examples of C ⁇ alkanoyl are formyl, acetyl, propionyl and butyryl; examples of halo are fluoro, chloro, bromo and iodo; examples of C ⁇ _4alkylamino are methylamino, ethylamino, propylamino and
  • Cj_6alkylS(O)p_ are methylthio, methylsulfinyl and methylsulfonyl;
  • examples of C ⁇ _4alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl;
  • examples of di(C ⁇ _4alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl;
  • examples of C ⁇ alkyl are methyl, ethyl, propyl and isopropyl;
  • C ⁇ _4alkoxycarbonylamino are methoxycarbonylamino and ethoxycarbonylamino; examples of
  • C ⁇ _4alkanoylamino are acetamido and propionamido; examples of C ⁇ _4alkanoyl(N-C 1 _4alkyl)amino are N-methylacetamido and N-methylpropionamido; examples of C ⁇ alkanesulfonamido are methanesulfonamido and ethanesulfonamido; examples of C]_4alkylaminosulfonyl are methylaminosulfonyl and ethylaminosulfonyl; examples of di(C ⁇ _4alkyl)aminosulfonyl are dimethylaminosulfonyl, diethylaminosulfonyl and ethylmethylaminosulfonyl; examples of Cj ⁇ alkanoyloxy are acetyl oxy and propionyloxy; examples of formylC ⁇ alkyl are formylmethyl and 2-formyle
  • C ⁇ _4alkoxyiminoC ⁇ _6alkyl are methoxyiminomethyl, ethoxyiminomethyl and
  • A is optionally substituted: phenyl, naphthyl, thiadiazolyl, thienyl, pyridyl or pyrimidyl.
  • B is optionally substituted: pyridyl, phenyl, thiazolyl, thienyl, pyridazinyl, or oxazolyl.
  • A is optionally substituted: phenyl or thienyl.
  • B is optionally substituted: pyridyl, phenyl, thienyl, pyridazinyl or thiazolyl.
  • A is optionally substituted phenyl.
  • B is optionally substituted: pyrid-2,5-diyl, pyridazin-3,6-diyl, phen-l,4-diyl or thien-2,5-diyl.
  • B is optionally substituted pyridazin-3,6-diyl or pyrid-2,5-diyl.
  • B is pyridazinyl
  • D when D is hydrogen, preferably B is optionally substituted: pyridyl, thienyl, pyridazinyl or thiazolyl;
  • Prefe ⁇ ed optional substituents for ring carbon atoms in A are halo, nitro, trifiuoromethyl, cyano, amino, Cj.galkoxy, carbamoyl, C ⁇ _4alkylcarbamoyl, di(C ⁇ _4alkyl)carbamoyl, C ⁇ _4alkanoylamino, C ⁇ .galkylS(O)p., C1.4alkanesulfonan.ido, benzenesulfonamido, C .galkanoyl, C ⁇ _4alkoxyiminoC ⁇ _4alkyl and hydroxyiminoCi ⁇ alkyl.
  • A is a 6-membered ring
  • A is unsubstituted or substituted in the
  • Preferred optional substituents for ring carbon atoms of B are halo, trifiuoromethyl, Cj. 4 alkyl, amino, C alkylamino, diC ⁇ alkylamino, nitro, hydroxy, C ⁇ alkoxy and cyano.
  • n 0;
  • A is unsubstituted or substituted by one substituent.
  • A is unsubstituted or substituted by bromo, methanesulfonyl, fluoro or chloro.
  • A is unsubstituted or substituted by bromo or chloro.
  • B is unsubstituted or substituted by one substituent.
  • B is unsubstituted.
  • R ⁇ is carboxy, carbamoyl or tetrazolyl or R! is of the formula
  • R a is hydrogen or Ci.galkyl and R a l is Ci.galkyl optionally substituted by hydroxy, C2_6 a lkenyl, 1-morpholinyl, 1-piperidinyl, 1-pyrrolidinyl, or Rl is of the formula -CONHSO2R ⁇ wherein R D is optionally substituted: Ci.galkyl, phenyl or 5- or 6-membered heteroaryl.
  • R! is carboxy, tetrazolyl or of the formula -CONR a R a l wherein R a is hydrogen and R a ⁇ is Ci.galkyl optionally substituted by hydroxy or pyridylmethyl, or R! is of the formula -CONHSO2 ⁇ wherein R D is C .galkyl (optionally substituted by hydroxy or fluoro), phenyl (optionally substituted by acetamido), isoxazolyl (optionally substituted by methyl) or 1,3,4-thiadiazolyl (optionally substituted by acetamido).
  • R is carboxy, tetrazole or of the formula -CONHR a ⁇ wherein R a ⁇ is pyridylmethyl or C _4alkyl optionally substituted by hydroxy, or of the formula
  • R b is C alkyl, 3,5-dimethylisoxazol-4-yl, or 5-acetamido-l,3,4- thiadiazol-2-yl.
  • R 1 is carboxy, carbamoyl or tetrazolyl or R 1 is of the formula -CONR a R al wherein R a is hydrogen or C ⁇ - 6 alkyl and R al is C
  • R 2 is hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, cyanomethyl, allyl or 3 -propynyl. More preferably R is hydrogen, methyl, ethyl or propyl.
  • R 2 is hydrogen or ethyl. Most preferably R 2 is ethyl.
  • R 3 is hydrogen
  • R 4 is optionally substituted by fluoro, chloro or bromo.
  • R 4 is optionally substituted by fluoro, trifiuoromethyl, cyano or hydroxy.
  • R 4 is C ⁇ _4alkyl, C 3 - 6 cycloalkyl or C 3 - 6 cycloalkylmethyl.
  • R 4 is propyl, isobutyl, butyl, 2-ethylbutyl, 2(R)-methylbutyl, 2(S)- methylbutyl, 2,2,2-trifluoroethyl, cyclopentylmethyl, cyclopropylmethyl, cyclopropyl or cyclopentyl.
  • R 4 is propyl, isobutyl, butyl, 2-ethylbutyl, cyclopentyl, cyclopropylmethyl or cyclopropyl;
  • R 5 is hydrogen or methyl.
  • R 6 is hydrogen, methyl or chloro.
  • R is hydrogen, methyl or chloro.
  • R 8 is hydrogen or methyl.
  • the 5-7 membered carbocyclic ring containing one double bond is optionally substituted by methyl.
  • D is a 5-6 membered carbocyclic ring containing one double bond (optionally substituted by methyl) methyl substituted by a 5-6 membered carbocyclic ring containing one double bond (optionally substituted by methyl) or of the formula
  • D is of the formula:
  • D is hydrogen
  • a preferred class of compounds is that of the formula IE or fo ⁇ nula IIE:
  • R! and R 2 and D are as hereinabove defined, R 4 of formula I is C1.4a.kyl, C 3 - 6 cycloalkyl or
  • R ⁇ is hydrogen or as hereinabove defined for substituents for ring carbon atoms in A
  • B is phenyl, thienyl, pyridazinyl, pyridyl, or thiazolyl.
  • Prefe ⁇ ed compounds of formula I for use in this invention are: N-propanesulfonyl-6-[N-(5-bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazine- 3-carboxamide (described as Example 14 in International Patent Application WO 97/00863);
  • a prefe ⁇ ed compound of formula II for use in the present invention is:
  • A' is an optionally substituted:
  • E is nitrogen or CH
  • F is nitrogen or CH
  • G is sulphur or oxygen
  • H is nitrogen or CH
  • the -CH(R 12 )N(R 1 ⁇ B-R 10 and -OCH(R 13 )-D' linking groups are positioned in a 1 ,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the -OCHR13" linking group (and therefore in the 3-position relative to the -CHR ⁇ NRI 1- linking group) is not substituted;
  • B 1 is an optionally substituted:
  • D' is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl;
  • RlO is positioned on ring B' in a 1,3 or 1,4 relationship with the -CH(R12)N(R.11)- linking group in 6-membered rings and in a 1,3-relationship with the -CH(R12)N(R1 1)- linking group in 5-membered rings and is carboxy, carboxyC ⁇ alkyl, tetrazolyl, tetrazolylC ⁇ _3 alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or R ⁇ is of the formula (IIIA), (IIIB) or (IIIC):
  • R 10 is of the formula -CONR e R e l or -C ⁇ _3alkylCONR e R e l wherein R e is hydrogen, Ci.galkyl, C3.7cycloa.kyl, C3_7cycloalkylC ⁇ _3alkyl, C5_7cycloalkenyl or
  • C5.7cycloalkenylC1_3a.kyl and R e is hydrogen, hydroxy or optionally substituted: C j .joalkyl, C .ioalkenyl, Ci.io lkynyl, C3_7cyc.oa.kyl, C3_7cycloalkylC ⁇ .6alkyl, C3_7cycloalkylC2-6alkenyl, C3_7cycloalkylC2-6 a l ynyl, C5_7cycloalkenyl,
  • R e is as hereinabove defined, R ⁇ is hydrogen or
  • C galkyl and R ⁇ is hydrogen, hydroxy or optionally substituted: C ⁇ _ ⁇ oalkyl, C2_io a l enyl, C2_ ⁇ o lkynyl, C3.7cycloa.kyl, C3_7cycloalkylC _6alkyl, C3_7cycloalkylC2_6 lkenyl, C3_7cycloalkylC2_6alkynyl, C5_7cycloalkenyl, C5_7cycloalkenylC _6alkyl, C5_7cycloalkenylC2_6 lkenyl, C5_7cycloalkenylC2_6 a lkynyl, 5- or 6-membered heteroaryl, 5- or 6-membered heteroarylCi.galkyl, 5- or 6-membered saturated or partially saturated heterocyclyl, 5- or 6-membered saturated or partially saturated heterocyclylCj.galkyl, or RS
  • C ⁇ _ lkyl (optionally substituted by hydroxy, cyano, nitro, amino, halo, C ⁇ _4alkanoyl, C .4alkoxy or trifiuoromethyl) C2_6 l enyl, C2_6 a l ynyl, C3_6cycloalkyl, C3_6cycloalkylC ⁇ _3alkyl, C3_6cycloalkylC2_3alkenyl, C5_6cycloalkenyl, C5_ cycloalkenylC ⁇ _3 alkyl, C5.6cycloalkenylC2_3alkenyl, phenylC ⁇ _3alkyl or 5- or 6-membered heteroarylC i _3alkyl;
  • Rl2 is hydrogen or C1.4a.kyl
  • R ⁇ 3 is hydrogen or C ⁇ _4alkyl
  • a 5- or 6-membered heteroaryl ring system is a monocyclic aryl ring system having 5 or 6 ring atoms wherein 1, 2 or 3 ring atoms are selected from nitrogen, oxygen and sulphur.
  • a 5- or 6-membered saturated or partially saturated heterocyclic (heterocyclyl) ring is a ring system having 5 or 6 ring atoms wherein 1, 2 or 3 of the ring atoms are selected from nitrogen, oxygen and sulphur.
  • Particular 5- or 6-membered monocyclic heteroaryl rings include pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, thiadiazolyl, thienyl, furyl and oxazolyl.
  • Particular 5- or 6-membered saturated or partially saturated heterocyclic ring systems include py ⁇ olidinyl, py ⁇ olinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl and mo ⁇ holinyl.
  • Particular substituents for ring carbon atoms in A' include halo, trifiuoromethyl, nitro, hydroxy, amino, C1_4alkylam.no, diC ⁇ _4alkylamino, cyano, C ⁇ _6alkoxy,
  • a ring nitrogen atom in A' can be substituted without becoming quaternized, it is unsubstituted or substituted by C1.4a.kyl.
  • Particular substituents for ring carbon atoms in B' include halo, amino, C1_4alkylam.no, di(C ⁇ _4alkyl)amino, trifiuoromethyl, nitro, hydroxy, C ⁇ _6alkoxy, C _ alkyl, amino, C1_4a.kylam.ino, di(C ⁇ _4alkyl)amino, cyano, -S(O)pC ⁇ _6alkyl (p is 0, 1 or 2), carbamoyl, Cj.4alkylcarbamoyl and di(C ⁇ _4alkyl)carbamoyl.
  • a ring nitrogen atom in B' can be substituted without becoming quaternized, it is unsubstituted or substituted by C ⁇ _4alkyl.
  • Particular substituents for optionally substituted groups in R e ⁇ , Rf and R n include those mentioned above for ring A'.
  • Particular substituents for carbon atoms in optionally substituted groups in R e ⁇ include halo, hydroxy, C ⁇ _4alkyl, nitro, cyano, amino, carboxy, trifiuoromethyl, C1.4a.koxy,
  • Particular substituents for optionally substituted groups in R ⁇ include halo, trifiuoromethyl, nitro, C1.4a.kyl, hydroxy, amino, cyano, amino, C ⁇ _6alkoxy, S(O)pC ⁇ _6alkyl (p is 0, 1 or 2), carbamoyl, C1.4alkylcarban.oyl, di(C ⁇ _4alkyl)carbamoyl, C2- lkenyl, C2_6alkynyl, C3_7cycloalkyl, C5_7cycloalkenyl, C3_7cycloalkylC ⁇ _3alkyl, C5_7cycloalkenylC ⁇ _3alkyl, C3_7cycloalkylC2_3alkenyl, C5_
  • alkyl when used herein includes straight chain and branched chain substituents for example methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl and functional groups on alkyl chains may be anywhere on the chain, for example hydroxyiminoC ⁇ _6alkyl includes l-(hydroxyimino)propyl and 2-(hydroxyimino)propyl.
  • C ⁇ _6alkoxycarbonyl examples are methoxycarbonyl, ethoxycarbonyl and t-butoxycarbonyl; examples of carboxyC1.3a.kyl are carboxymethyl, 2-carboxyethyl,
  • examples of C ⁇ _6alkoxycarbonylC 1.3 alkyl are methoxycarbonylmethyl, ethoxycarbonylmethyl and methoxycarbonylethyl; examples of tetrazolylC ⁇ _3 alkyl are tetrazolylmethyl and 2-tetrazolylethyl; examples of C ⁇ _4alkoxy are methoxy, ethoxy, propoxy and isopropoxy; examples of C2_6 a lkenyl are vinyl and allyl; examples of C2_6 a lkynyl are ethynyl and propynyl; examples of C ⁇ _4alkanoyl are formyl, acetyl, propionyl and butyryl; examples of halo are fluoro, chloro, bromo and iodo; examples of C ⁇ _4alkylamino are methylamino, ethyla
  • -S(O)pC ⁇ _4alkyl are methylthio, methylsulphinyl and methyl sulphonyl; examples of
  • C j _4alkylcarbamoyl are methylcarbamoyl and ethylcarbamoyl; examples of di(C ⁇ _4alkyl)carbamoyl are dimethylcarbamoyl, diethylcarbamoyl and ethylmethylcarbamoyl; examples of Ci ⁇ alkyl are methyl, ethyl, propyl and isopropyl; examples of C3.7cycloa.kyl are cyclopropyl, cyclobutyl and cyclohexyl; examples of C3_7cycloalkylC ⁇ _3alkyl are cyclopropylmethyl and cyclohexylmethyl; examples of C3_7cycloalkylC2-3alkenyl are cyclopropylethenyl and cyclopentylpropenyl; examples of C3_7cycloalkylC2-3alkynyl are cyclopropylethyn
  • Suitable ring systems of the formula (IIIA), (IIIB) or (IIIC) include 5-oxo-4,5-dihydro-l ,2,4-oxadiazole-3-yl, 3-oxo-2,3-dihydro-l ,2,4- oxadiazole-5-yl, 3-thioxo-2,3-dihydro-l,2,4-oxadiazole-5-yl, 5-oxo-4,5-dihydro-l,3,4-oxadiazole-2-yl, 5-oxo-4,5-dihydro- 1 ,2,4-triazole-3-yl, 3-oxo-2,3-dihydroisoxazole-5-yl, 5-oxo-l,5-dihydroisoxazole-3-yl and 5-oxo-2,3-dihydropyrazol-3-yl.
  • Amino acid residues formed from R e and R e ⁇ together with the amide nitrogen to which they are attached and esters thereof include for example radicals of the formula
  • Rg is hydrogen, Chalky., C2_6 lkenyl, C2_6 lkynyl, phenyl, phenylC ⁇ _3alkyl, 5- or 6-membered heteroaryl or 5- or 6-membered he.eroarylC1_3a.kyl and Rh is hydrogen or Cj. ⁇ alkyl, wherein alkyl, alkenyl, alkynyl, phenyl and heteroaryl groups are optionally substituted. Examples of substituents include those mentioned above for ring A'. In particular hydroxy.
  • alkenyl or alkynyl group When an alkenyl or alkynyl group is directly linked to the nitrogen of a primary or secondary amine it will be appreciated that the double or triple bond may not be in the 1 -position. Similarly alkyl groups which are substituted by halo, hydroxy or an amine may not be substituted by these substituents in the 1 -position when the alkyl group is directly linked to the nitrogen of a primary or secondary amine.
  • A' is an optionally substituted:
  • A' is optionally substituted:
  • A' is optionally substituted:
  • A' is optionally substituted phenyl.
  • B' is optionally substituted:
  • pyridyl phenyl, thiazolyl, thienyl, pyridazinyl, thiadiazolyl, imidazolyl, pyrazinyl, pyrimidyl, or oxazolyl.
  • B' is optionally substituted:
  • D' is optionally substituted: pyridyl, thienyl, thiazolyl, furyl or phenyl.
  • D' is optionally substituted: thienyl, furyl or phenyl.
  • D' is optionally substituted phenyl.
  • optional substituents for ring carbon atoms in A' are halo, nitro, trifiuoromethyl, cyano, amino, C ⁇ _6alkoxy, carbamoyl, Cj.galkyl, C3_7cycloalkyl,
  • substituents for ring carbon atoms in A' are chloro, bromo and methanesulphonyl.
  • A' is substituted on a ring carbon atom by bromo.
  • A is a 6-membered ring
  • A' is unsubstituted or substituted in the 4-position relative to the -O-CH(R ⁇ ). linking group.
  • Prefe ⁇ ed optional substituents for ring carbon atoms of B' are halo, amino, diC ⁇ _4alkylamino, C1_4alkylam.no, trifiuoromethyl, nitro, hydroxy, methyl, C ⁇ alkyl, C 1 _4alkoxy and cyano.
  • More preferred optional substituents for ring carbon atoms of B' are fluoro, chloro, bromo, trifiuoromethyl, hydroxy, methyl, methoxy and cyano.
  • D' is optionally substituted by 1 or 2 substituents selected from halo, trifiuoromethyl, nitro, hydroxy, amino, C 1 _4alkylam.n0, di(C ⁇ _4alkyl)amino, cyano, C ⁇ _6alkoxy, -S(O)pC ⁇ _4alkyl (p is 0, 1 or 2), Ci ⁇ alkanoyl, Ci.galkyl, C3.7cycloa.kyl,
  • C5_7cycloalkenyl, C ⁇ _6alkyl and C ⁇ _6alkyloxy are optionally substituted by trifiuoromethyl, hydroxy, halo, nitro, cyano or amino.
  • D' Most preferred optional substituents for D' include halo, nitro, hydroxy, cyano,
  • C ⁇ _6alkyl amino, C ⁇ _6alkoxy or carbamoyl.
  • D' is unsubstituted.
  • A' is unsubstituted or substituted by one substituent.
  • B' is unsubstituted or substituted by one substituent.
  • R ⁇ O is carboxy, carbamoyl, tetrazolyl or of the formula -CONR e R e l or -CONHSO2R f .
  • R e ⁇ is hydrogen, hydroxy or optionally substituted: Ci.galkyl,
  • cyclopentenyl cyclohexenyl, cycloheptenyl, cyclopentenylC ⁇ _4alkyl, cyclohexenylC ⁇ _4alkyl or cycloheptenylC ⁇ _4alkyl.
  • R e ⁇ is hydrogen, C ⁇ _6alkyl (optionally substituted by halo, hydroxy, nitro, cyano, amino, carboxy, C ⁇ _4_alkoxycarbonyl), pyridylC ⁇ _4alkyl, pyrimidylC ⁇ _4alkyl, pyrazinylCj ⁇ alkyl, furylC1.4a.kyl, pyridazinylC ⁇ .4alkyl, tetrazolylC _4alkyl, or C2_6alkenyl.
  • R e l is Cj_4alkyl (optionally substituted by one or two substituents selected from hydroxy, carboxy and C ⁇ _4alkoxycarbonyl), and furylC ⁇ _4alkyl.
  • -C ⁇ _ 3 alkylCONR e R el is -CH 2 CONR e R el .
  • -C ⁇ _3alkylCONHSO R f is -CH 2 CONHSO 2 R f .
  • -C ⁇ _ 3 alkylCONReNRgR h is -CH 2 CONR e NRgRh d .
  • Rf is optionally substituted: C ⁇ galkyl,
  • Rf is C1.4a.kyl (optionally substituted by hydroxy, nitro, cyano, amino, C ⁇ .4alkylamino, di-C ⁇ _4alkylamino, C ⁇ _4alkanoylamino, C1_4alkyl-N-C1_4alkanoylam.no, carbamoyl, C ⁇ _4alkylcarbamoyl, di-C 1 _4alkanoylcarbamoyl, halo, C 1 _4alkoxy) or optionally substituted phenylC 1 _3alkyl, pyridylC ⁇ _3alkyl, phenyl, thienyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl or 1 , 1 -dioxidotetrahydrothienyl.
  • Rf is C1.4a.kyl, hydroxyC1.4a.kyl, C ⁇ .4alkoxyC ⁇ .4alkyl, phenyl (optionally substituted by halo, cyano, nitro, carbamoyl, Cj.4alkylcarbamoyl, di-C ⁇ _4alkylcarbamoyl, hydroxy, amino, C ⁇ _4alkanoylamino,
  • benzyl (optionally substituted by halo, cyano, nitro, carbamoyl, C ⁇ _4alkylcarbamoyl, di-C ⁇ _4alkylcarbamoyl, hydroxy, amino, C ⁇ _4alkanoylamino, N-C ⁇ _4alkanoyl-N-C _4alkylamino, C1_4a.kylan.ino or di-(C ⁇ _4alkyl)amino), thiadiazolyl (optionally substituted by C 1 _4alkanoylamino, amino, C j _4alkylamino or di-C 1 _4alkylamino), thienyl (optionally substituted by halo or pyridyl), isoxazoly
  • R ⁇ is hydrogen and R n is 5- or 6-membered heteroaryl or RE and R n , together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated or partially saturated heterocyclic ring. More preferably R ⁇ is hydrogen and R n is pyridyl or RS and R n , together with the nitrogen atom to which they are attached, form mo ⁇ holino.
  • RlO is carboxy, carbamoyl or tetrazolyl or RlO is of the formula -CONR e R e * wherein R e is hydrogen or C ⁇ _6alkyl and R e is C ⁇ _6alkyl (optionally substituted by hydroxy), C2_ lkenyl, 1 -mo ⁇ holinyl, 1-piperidinyl, 1 -pyrrolidinyl, • pyridylC ⁇ _3alkyl or R ⁇ O is of the formula -CONHSO2R ⁇ wherein R ⁇ is C ⁇ galkyl or phenyl.
  • RlO j s carboxy, tetrazolyl or of the formula -CONR e R ⁇ l wherein R e is hydrogen and R e ⁇ is Ci.g lkyl (optionally substituted by hydroxy) or pyridylmethyl, or
  • R 10 is of the formula -CONHSO2R f wherein R f is Ci ⁇ alkyl or phenyl.
  • R ⁇ ® is carboxy
  • R! 1 is hydrogen, methyl, ethyl, cyclopropylmethyl, 2-fiuoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, cyanomethyl, allyl or 2-propynyl.
  • Rl 1 is ethyl, allyl or 2-propynyl.
  • R 1 is ethyl
  • R! 1 is hydrogen, C ⁇ _6alkyl (optionally substituted by hydroxy, cyano or trifiuoromethyl), C2-6 lkenyl, C2_6alkynyl, phenylC ⁇ _3alkyl or pyridylC ⁇ _3alkyl;
  • R ⁇ 2 1S hydrogen, methyl or ethyl.
  • R ⁇ 3 is hydrogen, methyl or ethyl.
  • R 1 ⁇ is hydrogen or methyl.
  • R ⁇ is hydrogen.
  • a preferred compound of formula III for use in this invention is:
  • R IA denotes a hydroxy, alkoxy group of C
  • R 2A denotes hydrogen atom or alkyl group of C ⁇ -C ,
  • R 3A and R 4A denotes alkyl group of Cj-C , halogen atom or trifiuoromethyl group,
  • R 5A denotes hydrogen atom, alkyl group of C ⁇ -C 4 , halogen atom or trifiuoromethyl group,
  • Y denotes cis-vinylene or trans-vinylene
  • ⁇ denotes single bond or double bond
  • Ring A2 and ring B2 each independently denote carbon-ring of C 5 -C ⁇ 5
  • Z 1 comprises a group represented by
  • R denotes a hydroxy group, C]-C 4 alkoxy or a group represented by formula NR B R 7B , wherein, R 6B and R 7B independently denotes hydrogen or C ⁇ -C alkyl; or
  • Z denotes hydrogen atom, Cj-C 4 alkyl, C]-C 4 alkoxy, nitro, halogen, trifiuoromethyl, trifluoro methoxy, hydroxy group or a group represented by formula COR 1 B , wherein, R 1 B has the same aforesaid meaning),
  • Z represents single bond or C ⁇ -C 4 alkylene
  • Z 4 represents SO or CO
  • Z 5 denotes (1) C,-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl,
  • phenyl, C 3 -C cycloalkyl, 5-7 membered heterocyclic ring having 1 or 2 oxygen, sulfur or nitrogen atoms may be substituted with 1-5 R 5B groups wherein a plurality of R 5B groups independently denote hydrogen atom, C ⁇ -C 6 alkyl, Cj-C 6 alkoxy, C ⁇ -C 6 alkylthio, nitro, halogen, trifiuoromethyl, trifluoro methoxy or hydroxy group)),
  • R 2B denotes CONR 8B , NR 8B CO,
  • R 8B denotes hydrogen atom or C ⁇ -C 4 alkyl
  • O, S, NZ 6 wherein, Z 6 denotes
  • R 3B denotes hydrogen atom, CpC 6 alkyl, C]-C 6 alkoxy, Cj-C 6 alkylthio, nitro, halogen, trifiuoromethyl, trifluoro methoxy, hydroxy group or hydroxymethyl,
  • R 4B denotes
  • phenyl, C 3 -C cycloalkyl may be substituted with 1-5 R 5B groups wherein R 5B has the same aforesaid meaning,
  • n and t respectively independently represent an integer of 1-4.
  • R 2 and R 3 each bond only at 1 and 2 position of ring B2
  • (Z 2 )t does not represent COR 1 B , Z 1 is bonded only at 3 or 4 positions of the benzene ring.
  • a method of reducing uric acid levels in a warmblooded animal which comprises administering to said animal a therapeutically effective amount of the compound described above, preferably the compounds of formula I, formula II, formula III, fo ⁇ nula IN or formula V above.
  • a method of treating hyperuricemia in a warm blooded animal such as a human being which comprises administering to said animal a therapeutically effective amount of the compound described above, preferably a compound of formula I, formula ⁇ , fo ⁇ nula III, fo ⁇ nula IV or fo ⁇ nula N above, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
  • a method of treating or preventing a disease caused by hyperuricemia in a warm-blooded animal comprising administering to the animal a therapeutically effective amount of the compound described above, preferably a compound of formula I, fo ⁇ nula II, fo ⁇ nula III, fo ⁇ nula IV or formula V above, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
  • the diseases that may be treated comprise hyperuricemia, gout, gouty arthritis, trophi, hyperuricemia associated with a congenital abnormality in the metabolism of xanthine oxidase, urate nephropathy incident to hyperuricemia, hyperuricemia incident to cytotoxic chemotherapy and hyperuricemia incident to radiation therapy.
  • Preferred compounds of the invention are those of formula I, formula II, formula III, formula IV and formula V above, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
  • a particularly prefe ⁇ ed compound is the compound: N-propanesulfonyl-6-[N-(5- bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof.
  • the compounds of the invention may exist in, and be isolated in, optically active or racemic form.
  • the invention includes any optically active or racemic form of a compound of the present invention which possesses uric acid reducing properties.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by, resolution of a racemic form, by synthesis from optically active starting materials or by asymmetric synthesis.
  • certain compounds of the present invention may exist as geometrical isomers.
  • the invention includes any geometrical isomer of a compound of the present invention which possesses uric acid lowering properties.
  • the present invention encompasses tautomers of the compounds of the formula I, formula II, formula III, fo ⁇ nula IN and fo ⁇ nula V.
  • compounds of the present invention will include pharmaceutically acceptable salts and ester derivatives which are hydrolysable in vivo.
  • pharmaceutically acceptable salts of compounds of the present invention may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound (or its ester) with a suitable acid to afford a physiologically acceptable anion. It may also be possible to make a conesponding alkali metal (e.g. sodium, potassium, or lithium) or alkaline earth metal (e.g. calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid (and in some cases the ester) with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g. the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in aqueous medium followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid (and in some cases the ester)
  • an alkali metal or alkaline earth metal hydroxide or alkoxide
  • An in vivo hydrolysable ester of a compound of the invention containing a carboxy group is, for example, a pharmaceutically acceptable ester which is hydrolysed in the human or animal body to produce the parent acid, for example, a pharmaceutically acceptable ester formed with a C ⁇ - 6 alcohol such as methanol, ethanol, ethylene glycol, propanol or butanol, or with a phenol or benzyl alcohol such as phenol or benzyl alcohol or a substituted or multiply substituted phenol or benzyl alcohol wherein the substituent is, for example, a halo (such as fluoro or chloro), C]. alkyl (such as methyl) or C ⁇ alkoxy (such as ethoxy) group.
  • ⁇ -acyloxyalkyl esters and related compounds which break down to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl esters include acetoxymethoxycarbonyl and 2,2-dimethylpropionyloxymethoxycarbonyl.
  • an EPl antagonist will generally be administered in the form of a conventional pharmaceutical composition, for example, as may be described in the relevant published European, US or International patent applications refe ⁇ ed to above, and generally the composition may be in a form suitable for oral or sublingual administration, for example as a tablet or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) for example as a sterile solution, suspension or emulsion, for topical administration for example as an ointment or cream or for rectal administration for example as a suppository.
  • parenteral injection including intravenous, subcutaneous, intramuscular, intravascular or infusion
  • a sterile solution, suspension or emulsion for topical administration for example as an ointment or cream or for rectal administration for example as a suppository.
  • the above compositions may be prepared in a conventional manner using conventional ca ⁇ iers.
  • the compositions of the present invention are advantageously presented in unit dosage form. Subsequent to administration
  • a therapeutically effective amount for the practice of the present invention may be determined, by the use of known criteria within the context of the disease which is being treated or which is being prevented, by one of ordinary skill in the art.
  • a suitable therapeutically effective dose of the compound will normally be administered to a warm-blooded animal within the range of 5-5000 mg per square meter body area of the animal, i.e., approximately 0.1-100 mg/kg.
  • a further feature of the invention is a pharmaceutical composition which comprises an EPl antagonist, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically acceptable carrier for reducing uric acid levels in a warm-blooded animal such as a human.
  • a pharmaceutically acceptable carrier for reducing uric acid levels in a warm-blooded animal such as a human.
  • composition which comprises an EP 1 antagonist, or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, in association with a pharmaceutically acceptable ca ⁇ ier for the treatment of hyperuricemia.
  • Treatment of a disease within the context of the present invention means to administer a an effective amount of a compound described for use in this invention, to mitigate either a pre-existing disease state, acute or chronic, or a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recu ⁇ ing conditions and continued treatment of chronic disorders.
  • Treatment further means to alleviate associated symptoms and signs of hyperuricemia. Examples of these symptoms include the precipitation of solid crystalline deposits of uric acid in soft tissues. These deposits may be in joint tissue associated with gout or gouty arthritis. The deposits may be in the microtubules of the kidney and associated with renal calculi, hyperuricemic nephropathy, urinary tract infections and renal insufficiency. The deposits may occur in other soft tissues as trophi.
  • Symptoms of infantile hyperuricemia may involve growth and motor retardation and sensorineural deafness.
  • the practice of the present invention may be for treatment of a pre-existing condition of hyperuricemia or a disease associated with hyperuricemia such as gout, by reducing uric acid levels.
  • Prevention of hyperuricemia and diseases associated with hyperuricemia means control of uric acid levels by prophylactic administration of compounds of the present invention in order to prevent hyperuricemia and to prevent diseases associated with hyperuricemia.
  • diseases associated with hyperuricemia are recu ⁇ ing conditions. It will be understood that the risk of occu ⁇ ence or recu ⁇ ence of diseases associated with hyperuricemia, or elevated levels of uric acid, is directly related to the degree of elevation of uric acid levels.
  • compounds of the present invention may be used in the prevention of recurring episodes of hyperuricemia or diseases associated with hyperuricemia, for example, by prophylactic dosing to control uric acid levels and prevent the hyperuricemia which is the underlying cause of diseases such as gout and gouty arthritis.
  • a method of lowering uric acid levels useful in treatment of hyperuricemia and diseases associated with hyperuricemia including, but not limited to, gout, gouty arthritis, trophi, hyperuricemia associated with a congenital abnormality in the metabolism of xanthine oxidase, urate nephropathy incident to hyperuricemia, or hyperuricemia incident to therapeutic use of cytotoxic chemotherapy.
  • a method of preventing subsequent elevated uric acid levels as prophylactic therapy to prevent the recurrence of hyperuricemia and diseases associated with hyperuricemia including, but not limited to, gout, gouty arthritis, trophi, hyperuricemia associated with a congenital abnormality in the metabolism of xanthine oxidase, urate nephropathy incident to hyperuricemia, or hyperuricemia incident to therapeutic use of cytotoxic chemotherapy, comprising prophylactic therapy or combination therapy of uric acid lowering agent with said cytotoxic agents or radiation therapy.
  • Compounds of the present invention may additionally be used as preventative therapy involving a combination therapy comprising co-administration of compounds or pharmaceutical compositions of the present invention with cytotoxic agents or radiation therapy for the treatment of cancers, including lymphomas, leukemia, and solid tumors, said co-administration being for the treatment or prevention of hyperuricemia associated with the administration of said cytotoxic agents or radiation therapy.
  • a method of preventing elevation of uric acid levels, associated with administration of cytotoxic agents or radiation therapy involved in the treatment of cancers, including lymphomas, leukemia, and solid tumors comprising coadministration of an EPl antagonist with said cytotoxic or radiation therapy.
  • a method of preventing elevation of uric acid levels, associated with administration of cytotoxic agents or radiation therapy involved in the treatment of cancers, including lymphomas, leukemia, and solid tumors comprising coadministration of a compound of formula I, formula II, formula III, formula IV or formula V described above with said cytotoxic or radiation therapy.
  • EPl antagonists of the present invention may be used to reduce uric acid levels in single therapeutic agent therapy or in combination therapy.
  • Combination therapy may involve cu ⁇ ent conventional therapeutic agents used in the management of hyperuricemia.
  • Such combination therapy may involve concomitant use of a conventional therapeutic uricosuric agent such as probenecid or sulfinpyrazone, or in combination with agents known to inhibit the biosynthesis of uric acid, such as allopurinol.
  • therapy may be effected in combination with such conventional therapies as NSAIDS, such as indomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam; or colchicine; or corticosteroids such as methylprednisolone which address the inflammation associated with crystalline deposits of uric acid in conditions such as gout or gouty arthritis.
  • NSAIDS such as indomethacin, ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam; or colchicine
  • corticosteroids such as methylprednisolone which address the inflammation associated with crystalline deposits of uric acid in conditions such as gout or gouty arthritis.
  • Combination therapy may also involve an opiate.
  • Combination therapies may also employ strategies such as hydration, osmotic diuresis and urinary al
  • Example is illustrative only, and is not meant to limit this invention in any manner.
  • Test subjects were orally administered tablets containing N-propanesulfonyl-6-[N-(5- bromo-2-(cyclopropylmethoxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide, or a matching placebo was administered orally as tablets, with 200 mL of distilled water. The subjects were directed to remain semi-recumbent for six hours after dosing. A 4.9 mL sample of blood was taken into a tube containing lithium heparin anticoagulant, and plasma was separated by centrifugation for the clinical chemistry analysis at the pretrial medical examinations, pre-dose, 6 hours and 24 hours after dosing on each trial day. Concentrations of the uric acid were determined by standard analytical techniques. The data gathered on compounds of the present invention is depicted in Table 1 below.
  • Table 1 Clinical data for reduction of uric acid levels in human volunteers.
  • the listed percentages represent mean blood level of uric acid at 24 hours after administration of the test substance (active compound or placebo) as a percentage of the baseline uric acid level measured prior to administration.
  • the data demonstrates substantial reduction in serum levels of uric acid in a well-defined dose-dependent manner. In particular at a dose of 400 mg the mean uric acid blood level is reduced by 29%. Doses of 800mg and 1600 mg likewise reduce blood levels of uric acid by 33% and 42% respectively.

Abstract

L'invention concerne des agents thérapeutiques et, en particulier, l'utilisation de composés tels que des antagonistes EP1 pour réduire les niveaux d'acide urique chez les animaux à sang chaud comme les humains. La présente invention porte également sur une méthode pour réduire l'acide urique des animaux à sang chaud, consistant à administrer à ces animaux une dose efficace d'un antagoniste EP1. Les antagonistes EP1 sont des composés antagonistes aux prostaglandines de type E.
EP02704036A 2001-03-13 2002-03-13 Methode de traitement Withdrawn EP1370266A1 (fr)

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WO2002072098A1 (fr) 2002-09-19
WO2002072098A8 (fr) 2004-05-06
JP2004520433A (ja) 2004-07-08
SE0100873D0 (sv) 2001-03-13
US20040102524A1 (en) 2004-05-27

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